Human X-linked hyper-IgM syndrome is characterized by an elevated level of serum IgM and diminished (virtually undetectable) levels of other isotypes of immunoglobulins. Affected males usually experience onset of recurrent infection in the first year of life. The clinical course may include intermittent neutropenia and Pneumocystis pneumonia, as well as infections that are more typical of hypogammaglobulinemia, such as bacterial otitis, sinusitis, and pneumonia. This condition is lethal in the absence of medical intervention; however, patients typically respond well to a maintenance therapy consisting of intravenous gamma globulin, especially if therapy is initiated soon after birth.
Affected males have normal numbers of circulating B and T lymphocytes, although lymph node hyperplasia with an absence of germinal centers is common (Notarangelo et al., Annu. Rev. Immunol. 10:215, 1992). B-cells from such patients appear to be normal in that they can be induced to undergo isotype switching when cultured in vitro with a T cell line known to induce class switching in normal B-cell cultures (Hendricks et al., Eur. J. lmmunol. 20:2603, 1990; Mayer et al., N. Engl. J. Med. 314:409, 1986).
Elevated levels of serum IgM occur in other syndromes, including combined variable immune deficiency (CVID) and post congenital rubella. Alterations of T-cell activation either as a result of primary genetic immune deficiency or acquired CD4+ T-cell abnormality (e.g. AIDS) may also cause loss of CD40L-induced B-cell activation signals and thus partially explain the secondary abnormalities of B-cell function observed in these conditions.
The CD40 cell surface antigen has been shown to play an important role in B-cell proliferation and differentiation. Human CD40 protein (CD40), a cell-surface antigen present on the surface of B cells, is a peptide of 277 amino acids having a molecular weight of 30,600, with a 19 amino acid secretory signal peptide comprising predominantly hydrophobic amino acids. A cDNA encoding human CD40 was isolated from a cDNA library prepared from Burkitt lymphoma cell line Raji (Stamenkovic et al., EMBO J. 8:1403, 1989).
Activated CD4+ T cells express high levels of a ligand for CD40 (CD40L). Human CD40L, a membrane-bound glycoprotein, has recently been cloned from peripheral blood T-cells as described in Spriggs et al., J. Exp. Med. 176:1543 (1992), and in U.S. Patent application Ser. No. 07/969,703, filed Oct. 23, 1992, the disclosure of which is incorporated by reference herein. The cloning of murine CD40L is described in Armitage et al., Nature 357:80, 1992. CD40L induces B-cell proliferation and secretion of various immunoglobulin isotypes (except IgE) in the absence of any co-stimulus, and can also induce production of IgE in the presence of cytokines.
CD40L thus appears to play a critical role in the cognate interaction between CD4+T helper cells and B cells. A more detailed analysis of patients with X-linked hyper IgM syndrome and its related syndromes will provide valuable information on the T cell-B cell interactions involved in the humoral immune response. Early detection of X-linked hyper IgM syndrome and its related syndromes will allow prompt initiation of appropriate therapy. Therefore, them is a need in the art to develop methods of detecting and confirming X-linked hyper IgM syndrome and other abnormalities in B cell-T cell interactions in which CD40 and CD40L play a role. Alternative methods of treatment of such syndromes are also needed.